Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH3:12])[C:6]=2[CH:13]=1.COC(O)C.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1.Cl.O1CCOCC1.N>CO.ClCCl>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH3:12])[C:6]=3[CH:13]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCNCc2ccc(N)cc21
Agent: COC(C)O
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CN1CCNCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To 40 ml sure-seal reaction vial, 8-Amino-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepine (0.33 g, 2 mmoles), methoxy ethanol (6 ml), and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.51 g, 1.1.5 mmole), 4M HCl in dioxane (1 ml, 4 mmoles) were added. The reaction was heated to reflux for 3 hours. Upon cooling to room temperature, the solvent was then removed under vacuum to afford a yellow solid. The product (0.53 g, 74% yield) was isolated via column chromatography with dichloromethane and ammonia in methanol (2% to 30% ammonia in methanol) as eluant. NMR 1H-(DMSO)-δ-9.02 (bs, 1H), 7.93 (s, 1H), 7.32 (d, 1H, J=8.59 Hz), 7.16 (bs, 2H), 6.93 (d, 1H, J=7.58), 6.67 (d, 1 h, J=7.58 Hz), 3.80-3.90 (bm, 1H), 3.64 (s, 2H), 3.30-3.40 (bm, 1H), 3.17 (d, 1H, 5.2 Hz), 2.92 (s, 3H), 2.83-2.90 (m, 4H), 2.82 (s, 3H), 1.95-2.12 (m, 2H), 1.65-1.75 (m, 2H), 1.15-1.48 (m, 4H). LCMS (ESI+) 480.13 (M+H); MP=153-206° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30]N)[CH3:26].Cl.C(=O)([O-])[O-].[K+].[K+].C(#[N:42])C>O>[CH2:25]([O:27][C:28](=[O:32])[CH:29]([NH:42][CH2:2][C:3](=[O:4])[N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[CH3:30])[CH3:26]
Reactant: O=C(CCl)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Reactant: CC#N
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(C)NCC(=O)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Yield: 10 %

Procedure:
A mixture of crude 2-chloro-1-[5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-ethanone (80 mg, 0.22 mmol), 3-amino-propionic acid ethyl ester as HCl salt (68 mg, 0.44 mmol) and potassium carbonate (98 mg, 0.71 mmol) in acetonitrile (2 mL) was heated to reflux for 4 hrs. The mixture was treated with water and extracted with ether. The organic phase was dried over MgSO4, concentrated, and purified via a silica gel column to give desired product (11 mg, yield 10%). ESI-MS: 443.20 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]2[CH2:17][O:16]2)=[CH:11][C:10]=1[S:20]([CH2:22][CH2:23][CH2:24][CH3:25])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S(CCCC)=O)CCC.S(C1C=CC([N+]([O-])=O)=CC=1)(OC[C@H]1OC1)(=O)=O.Cl.[NH2:54][C@H:55]1[CH2:60][CH2:59][C@H:58]([C:61]2[CH:75]=[CH:74][C:64]([O:65][C:66]([CH3:73])([CH3:72])[C:67]([O:69][CH2:70][CH3:71])=[O:68])=[CH:63][CH:62]=2)[CH2:57][CH2:56]1>C(O)C.CO>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]([OH:16])[CH2:17][NH:54][C@H:55]2[CH2:60][CH2:59][C@H:58]([C:61]3[CH:62]=[CH:63][C:64]([O:65][C:66]([CH3:72])([CH3:73])[C:67]([O:69][CH2:70][CH3:71])=[O:68])=[CH:74][CH:75]=3)[CH2:57][CH2:56]2)=[CH:11][C:10]=1[S:20]([CH2:22][CH2:23][CH2:24][CH3:25])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc([C@H]2CC[C@H](N)CC2)cc1
Reactant: CCCCS(=O)c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Agent: CCCCS(=O)CCCC
Agent: Cl
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Solvent: CO
Solvent: CCO
Product: CCCCS(=O)c1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(OC(C)(C)C(=O)OCC)cc3)CC2)ccc1OCc1ccccc1

Procedure:
A mixture of 0.742 g of (2S)-2-{[4-(benzyloxy)-3-(butylsulfinyl)phenoxy]methyl}oxirane (obtained by analogy with the method disclosed in WO 99/65895 but starting from the butyl sulfoxide instead of the methyl sulfoxide and using (S)-(+)-glycidyl nosylate; [α]D=+1.9 (c=1%, MeOH)) (2.06 mmol) and of 0.666 g of ethyl trans-2-[4-(4-aminocyclohexyl)phenoxy]-2,2-dimethylacetate hydrochloride (2.18 mmol) in ethanol (25 ml) is heated to reflux overnight. The solvent is evaporated under reduced pressure and the product obtained is purified by flash chromatography, elution being carried out with a methylene chloride/methanol/aqueous ammonia (95/5/0.5) mixture. The title product is obtained in the form of a yellow oil (0.730 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[CH2:23][CH2:22]3)=[CH:18][CH:19]=[CH:20][C:13]1=2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[ClH:1].[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([N:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][O:30][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)[CH2:25][CH2:26]3)=[CH:18][CH:19]=[CH:20][C:13]1=2
Reactant: Clc1ccnc2ccccc12
Reactant: OCCCN1CCN(c2cccc3sccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: c1ccc2c(OCCCN3CCN(c4cccc5sccc45)CC3)ccnc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
4-Chloroquinoline (230 mg, 1.58 mmol), 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol (310 mg, 1.05 mmol), and potassium carbonate (220 mg, 1.6 mmol) were added to dimethylformamide (10 ml), followed by stirring at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, then water was added thereto and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure after filtration. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=4:1), and concentrated under reduced pressure. The resulting residue was dissolved in ethanol (3 ml), and 1N—HCl—ethanol solution (1 ml) was added thereto. Insoluble matters produced were filtered out and dried to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinoline hydrochloride (360 mg, yield: 78%) as light yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C(O)/C=C/c1cc(O)ccc1Br
Reactant: CCO
Product: CCOC(=O)/C=C/c1cc(O)ccc1Br
Yield: 90 %

Procedure:
A solution of acrylic acid 8 (4.35 g, 18.0 mmol) in dry ethanol (50 mL) with a small quantity of acid resine DOWEX™ (300 mg) was refluxed for 24 h. The reacion mixture was filtered, the solvent was evaporated in vacuo and the crude reaction product was purificated by means of chromatography on silica gel (hexane/AcOEt 10:1) to give 4.36 g of ester 9 as a white solid. Yield 90%. 1H RMN (300 MHz, CD3COCD3) δ ppm: 8.82 (br s, 1H), 7.94 (d, J=16.1 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.28 (d, J=2.9 Hz, 1H), 6.88 (dd, J1=8.7 Hz, J2=2.9 Hz, 1H), 6.45 (d, J=16.1 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H); 13C RMN (75 MHz, CD3COCD3) δ ppm: 167.5, 159.1, 144.0, 136.7, 135.9, 123.0, 121.3, 116.2, 115.8, 62.1, 15.6; HRMS (EI) m/z: calcd for C11H11BrO3: 269.9892. found: 269.9886; mp: 96-98° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=1O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:38]1[CH:37]=[C:34]([C:35]#[N:36])[CH:33]=[CH:32][C:31]=1[O:30][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(C#N)ccc1OCc1ccccc1)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.8 g (15.5 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 ml of tetrahydrofuran. 2.9 g (12.9 mmol) of 4-benzyloxy-3-hydroxybenzonitrile, 4.1 g (15.5 mmol) of triphenylphosphine and 6.7 g (15.5 mmol) of diethyl azodicarboxylate were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][O:14][CH2:15][N:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18][C:17]2=[O:23])=[CH:11][CH:10]=1>CO.C(Cl)(Cl)Cl>[OH:7][CH2:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][O:14][CH2:15][N:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18][C:17]2=[O:23])=[CH:11][CH:10]=1
Reactant: O=c1ncc(Cl)cn1COCc1ccc(COC2CCCCO2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ncc(Cl)cn1COCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
Dowex 50W-X8 ion exchanger in the acid form (0.29 g) was added to a solution of 1-[4-(tetrahydropyran-2-yloxymethyl)benzyloxy]methyl-5-chloropyrimidin-2-one (see Example 19) (1.2 mmol) in methanol (2 ml) and chloroform (0.5 ml) and the mixture stirred at room temperature for 2.5 hours. The ion exchanger was then removed by filtration and the filtrate evaporated to dryness at reduced pressure without heating. The residue was the title compound in the form of a non-crystalline material, obtained in 60% yield. 1H NMR (CDCl3): δ4.5-5.0 (2CH2), 5.38 (NCH2), 7.43 (Ph), 8.00 and 8.60 (H-4, H-6, J 4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][C:14]1=[O:19].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1COCCN1
Reactant: BrCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COCCN1CCCOc1ccc(Br)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 31.2 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and morpholin-3-one (100 mg, 1.02 mmol) in DMF (6 mL) was added NaH (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (100 mg, 35%) as a yellow oil.
Reaction SMILES: [OH-:1].[K+].C(O)C[OH:5].[Cl:7][C:8]1[C:12]([CH3:13])=[CH:11][S:10][C:9]=1[C:14]1([C:19]#N)[CH2:18][CH2:17][CH2:16][CH2:15]1.CCOCC>O>[Cl:7][C:8]1[C:12]([CH3:13])=[CH:11][S:10][C:9]=1[C:14]1([C:19]([OH:5])=[O:1])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCCO
Reactant: [OH-]
Reactant: Cc1csc(C2(C#N)CCCC2)c1Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Cc1csc(C2(C(=O)O)CCCC2)c1Cl
Temperature: 190 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (1.36 g) was added to an ethylene glycol (20 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbonitrile and the whole was stirred at 190° C. for 2 hours. After the reaction solution and ether were added to water, the aqueous layer was separated. An 1M aqueous hydrochloric acid solution was added to the aqueous layer to acidify the liquid and, after ether was added, the organic layer was separated. The layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure to obtain 1.59 g of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarboxylic acid (pale brown solid).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:11]([C:3]1[CH:4]=[CH:5][CH:9]=[CH:10][C:2]=1[OH:1])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 4-hydroxy-3nitrobenzoic acid (1a) (1 g, 5.46 mmol), HOBt (1 g 7.4 mmol), DIC (1,3-diisopropylcarbodiimide, 1 mL, 6.4 mmol), and a MP resin (1 g, 0.99 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:13]1([OH:17])[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.[N:25]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>ClCCl>[CH:13]1([O:17][C:2]([N:28]2[CH2:29][CH2:30][N:25]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:26][CH2:27]2)=[O:4])[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(C(=O)OC2CCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.6 g triphosgene and 1.7 ml cyclobutanol in 40 ml dichloromethane were added 6.2 ml triethylamine dropwise at 0° C. After 30 minutes 4.4 ml benzyl 1-piperazinecarboxylate and 3.2 ml triethylamine were added at 0° C. The reaction mixture was allowed to warm to RT for 16 h. Excess triphosgene was destroyed by adding a solution of 2 g NaOH in 200 ml water and stirring for 2 h. The layers were separated, the organic layer dried over MgSO4 and concentrated. The crude product thus obtained was purified by chromatography on silica using heptane/ethyl acetate 4/1 to 2/1 as eluent. Yield: 5.9 g.
Reaction SMILES: C12(COC3C(Cl)=CC(C(NS(N4CC[C@H](OCC5C=CC(OC)=CC=5)C4)(=O)=O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:42]1([CH2:48][O:49][C:50]2[C:76]([CH:77]3[CH2:79][CH2:78]3)=[CH:75][C:53]([C:54]([NH:56][S:57]([N:60]3[CH2:64][CH2:63][C@H:62]([O:65]CC4C=CC(OC)=CC=4)[CH2:61]3)(=[O:59])=[O:58])=[O:55])=[C:52]([F:80])[CH:51]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH:42]1([CH2:48][O:49][C:50]2[C:76]([CH:77]3[CH2:78][CH2:79]3)=[CH:75][C:53]([C:54]([NH:56][S:57]([N:60]3[CH2:64][CH2:63][C@H:62]([OH:65])[CH2:61]3)(=[O:58])=[O:59])=[O:55])=[C:52]([F:80])[CH:51]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: COc1ccc(CO[C@H]2CCN(S(=O)(=O)NC(=O)c3cc(C4CC4)c(OCC4CCCCC4)cc3F)C2)cc1
Agent: COc1ccc(CO[C@H]2CCN(S(=O)(=O)NC(=O)c3cc(Cl)c(OCC45CC6CC(CC(C6)C4)C5)cc3F)C2)cc1
Product: O=C(NS(=O)(=O)N1CC[C@H](O)C1)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 124 step 3 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-(((S)-3-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)sulfonyl)benzamide with (S)-4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)sulfonyl)benzamide, the title compound was obtained as colorless solid (0.14 g, 78%): 1H NMR (300 MHz, CDCl3) δ 8.86-8.76 (m, 1H), 7.58-7.46 (m, 1H), 6.63-6.48 (m, 1H), 4.55-4.35 (m, 1H), 3.92-3.77 (m, 3H), 3.71-3.59 (m, 3H), 2.48 (br s, 1H), 2.13-1.96 (m, 3H), 1.95-1.67 (m, 6H), 1.42-1.02 (m, 5H), 0.98-0.85 (m, 2H), 0.69-0.57 (m, 2H); MS (ES+) m/z 441.1 (M+1).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.C(Cl)CCl>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](=[O:5])[NH:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 5.00 g Z-Pro-OH in 50 ml DMF were added 3.84 g EDC, 2.73 g HOAt, 7.3 ml DIPEA and 2.2 ml benzylamine at 0° C. After stirring for 2 h the reaction mixture was concentrated, the residue was dissolved in dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was pure enough for the subsequent transformation.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH2:6][CH:7]1[CH2:13][CH:12]2[N:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=3)[CH:9]([CH2:10][CH2:11]2)[CH2:8]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([N:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:8][CH:7]([NH:6][C:1](=[O:3])[CH3:2])[CH2:13]3)=[CH:16][CH:17]=1)#[N:26]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)NC1CC2CCC(C1)N2c1ccc(C#N)c2ccccc12
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a −30° C. solution of acetyl chloride (15 μL, 0.21 mmol) in DMF (1.5 mL) was added dropwise a solution of 165RL21 (54 mg, 0.20 mmol) and DIPEA (37 μL, 0.21 mmol) in DMF (3.5 mL). After 1 hour of stirring the reaction mixture was brought to rt and allowed to react overnight. Water (20 mL) was then added and the mixture extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel using ethyl acetate/MeOH (9:1) to give the desired compound (35 mg, 56%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:3]1.C([O-])(=O)C.[Na+].[Br:27]Br.C(Cl)Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([Br:27])=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:3]1
Reactant: BrBr
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1scc(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(Br)c(Cl)c1Cl
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a mixture of 1-methyl-3-(2-chloro-6-fluorophenyl)-5-(3,4-dichlorothien-2-yl) [1,2,4]triazole (33.4 g, 92.1 mmol) and sodium acetate (7.6 g, 92.1 mmol) in acetic acid (250 mL) was added bromine (58.9 g, 368.4 mmol) dropwise at a rate which maintained the reaction temperature below 35° C. The resulting mixture was slowly heated to 70° C. and stirred for 2.5 hours, cooled to 50° C. and stirred overnight, and cooled to room temperature. TLC analysis (methylene chloride) indicates full consumption of the starting material. The reaction was slowly poured into a mixture of 10% aqueous sodium bisulfite and ice (300 mL), and the resulting pale yellow suspension was stirred for 20 minutes. The solids were collected by vacuum filtration, washed with water, and dissolved in methylene chloride. The organics were dried (sodium sulfate), filtered, and the solvent evaporated at reduced pressure to give 39.3 g (96%) of desired product as a tan solid: mp 178-180° C. 1H NMR (CDCl3) δ4.04 (s, 3H), 7.08-7.14 (Ar-m, 1H), 7.29-7.40 (Ar-m, 2H).
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring ice-cold solution of tert-butyl 4-(propylsulfonyl)piperazine-1-carboxylate (2, 15.70 g, 53.69 mmol) in CH2Cl2 (200 mL) was slowly added trifluoroacetic acid (21.4 mL, 268.45 mmol). The mixture stirred at room temperature for 16 h under an atmosphere of N2. The mixture was washed with 2 N NaOH (3×50 mL), H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 1-(propylsulfonyl)piperazine (3) as a crystalline solid (10.30 g quantitative): 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J=1.7 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.21 (m, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=O.[NH2:12]C(O)C.[C:16]([OH:19])(=O)[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][NH:12][CH2:17][CH2:16][OH:19])[CH:8]=[CH:9]1
Reactant: CC(=O)O
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CC(N)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OCCNCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-formyl indole (2.4 g, 16.6 mmol) in 1,2-dichloroethane (60 mL) was added aminoethanol (1.2 mL, 19.8 mmol) followed by glacial acetic acid (2.0 mL) and sodium triacetoxyborohydride (3.5 g, 16.6 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched by addition of water (10 mL) and 1.0 M sodium hydroxide (10 mL). The organic layer was then separated and the aqueous layer extracted with 1,2-dichloroethane (40 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2×30 mL), water (2×50 mL), dried over anhydrous sodium sulfate and evaporated to dryness. 2-[(1H-indol-7-ylmethyl)-amino]-ethanol (4.4 g) was obtained as an oil LCMS (M+H)=189.
Reaction SMILES: C[Mg]Br.[NH2:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([O:12][C:13]2[C:14]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=2)=[CH:7][N:6]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC>C1COCC1>[NH2:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([O:12][C:13]2[C:14]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19]([OH:21])([CH3:27])[CH3:20])[CH:18]=2)=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)=O
Agent: C[Mg]Br
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)(C)O
Temperature: 0 °C
Yield: 45.5 %

Procedure:
To a solution of methylmagnesium bromide (83.4 mmol, 27.8 ml, 3.0 M in Et2O) in 83 mL THF at 0° C. was added 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone (2.523 g, 8.3 mmol, from Example 16) in portions. After 16 h the mixture was cooled to 0° C. and was quenched by the addition 10% NH4Cl. H2O was added and the mixture was extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried over NaHCO3, filtered and concentrated in vacuo. The crude solid was taken up in 31 ml DMF. K2CO3 (0.65 g, 4.7 mmol) and iodomethane (0.098 ml, 1.6 mmol) were added and the mixture was warmed to 50° C. Additional portions of iodomethane (0.019 mL, 0.6 mmol) was added at 1, 2 and 3 hr. After 16 h the mixture was cooled and 10% NH4Cl and extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give 2-[5-(2,4-diaminopyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-propan-2-ol (0.711 g, yield) as a white solid. [MH]+=333.